An estimated 170 million people throughout the world are infected with the hepatitis C virus (HCV). More than 70% of these individuals remain chronically infected for life, of which 15-20% eventually develops liver cirrhosis and hepatocellular carcinoma. The current therapy for HCV infections is the combination of ribavirin and interferon-α (IFN-α), as well as a limited number of protease inhibitors (e.g. telaprevir or boceprevir). Unfortunately, in addition to severe side effects, the sustained response rate of this therapy is no better than about 80% and it is genotype-dependent.
More recently, a new nucleotide analog drug, sofosbuvir (isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate; brand name Sovaldi®) has been approved as the first all-oral, interferon-free treatment for treating chronic HCV infections. Sofosbuvir inhibits NS5B, the virus-encoded RNA-dependent RNA polymerase that replicates the RNA genome of HCV. In 2013, the FDA approved sofosbuvir in combination with ribavirin for oral dual therapy of HCV genotypes 2 and 3, as well as for triple therapy with injected pegylated interferon-α (pegIFN) and ribavirin for treatment-naive patients with HCV genotypes 1 and 4. Although, the clinical responses seen with sofosbuvir, alone and in combination therapy, are encouraging, further research is required to provide further options in the clinical arsenal to combat the widespread infections of HCV.
Accordingly, new and improved HCV treatments remain urgently needed to combat the widespread infections of HCV, including more selective and potent drugs with improved toxicity profiles that can be used alone or as part of combination therapy regimens. This need and other needs are addressed by the present invention.